PROJECT SUMMARY/ABSTRACT The central theme of the Developmental Therapeutics Program (DTP) is to practice the principles of precision therapy, identifying new targets within the pathophysiology of a malignancy to develop novel agents that block their functions and apply these agents to clinical trials in patients whose malignancies exhibit the biomarkers signifying the presence or activity of the target protein or pathway. The program has 47 members (33 primary and 14 associate) from 13 departments and is led by William Plunkett, who has developed multiple anti- leukemic agents in the laboratory; Funda Meric-Bernstam, a physician-scientist who leads the phase 1 department; Giulio Draetta, a physician-scientist who has extensive experience in drug development; and James Yao, a clinical trialist who has developed multiple targeted therapies. The program is organized around 4 major themes: 1) Discovery and Validation of Novel Targets, 2) Development of Novel Therapies, 3) Conduct of Proof-of-Principle Clinical Trials, and 4) Development of Therapies for Rare Cancers. Each theme is addressed by a specific aim. Aim 1: To identify and validate novel targets relevant to the molecular biology of tumors; Aim 2: To develop agents against new targets individually and in combination therapies; Aim 3: To conduct biomarker-driven trials with first-in-human agents or novel combinations; and Aim 4: To identify novel therapies for rare tumors. Annual direct peer-reviewed funding totals $10,284,482, of which $2,839,686 (28%) is from NCI grants, which is an increase of 109% in program annual direct peer-reviewed cancer-related funding since the last competitive renewal. Since the last submission, DTP members have authored 1048 publications: 454 (43%) represent intra-programmatic collaborations, 681 (65%) represent inter-programmatic collaborations, and 645 (62%) were inter-institutional collaborations. Fifty-nine percent of publications appeared in journals with IF >5, and 23% appeared in journals with IF >10, including Blood, Cancer Cell, Cancer Discov, Cell, JAMA, J Clin Invest, J Natl Cancer Inst, J Clin Oncol, Lancet, Lancet Oncol, Mol Cell, and Nature. During the last grant period, several novel targets were identified, including miR-155 in lung cancer, S-phase kinase-associated protein 2 ubiquitin ligase, and the susceptibility of tumors that depend on oxidative phosphorylation for survival. Importantly, novel agents to inhibit each of these targets have been discovered by DTP members and are currently in development. New agents include those that target miR-155, deficiency, the platinum exporter in ovarian cancer, BLy3 in lymphoma, c-Kit, JAK2, and STAT3. DTP members have identified tumors that require oxidative phosphorylation for their growth and have created a candidate inhibitor that is presently in clinical trials. Drugs matched with activating mutations in the PI3K pathway increased phase 1 response rates from 6% to 27% and increased the time before treatment failure. The 15-year analysis of the first chemoimmunotherapy trial in previously untreated CLL revealed prognostic factors associated with the first cures of this disease (37%), guiding the design of single-institution investigator-initiated trials that incorporate new targeted agents.